Gene Therapy for Cystic Fibrosis
Cystic fibrosis is a inherited recessive disease that causes a thick mucus to build up on the lungs, pancreas and small intestine. This mucus causes it to be difficult to breath, poor digestion, and increased vulnerability to infections. Cystic fibrosis is one of the most common lung diseases in children and young adults. Untreated, this could lead to a fatal lung infection at a young age. Genetic cause of CF The cells that line the airways in the lungs produce the abnormal mucus due to a mutation in the Cystic Fibrosis Transmembrane conductase Regulator gene found on chromosome 7. This mutation in the CFTR gene is normally a 3 base-pair deletion which codes for Phe. In a normal cell the CFTR gene helps to create an ion gradient by becoming a chloride channel. However when the gene is mutated it then mutates the channel causing it to not transport chloride ions across the membrane. This results in less chloride moving across the channels into the mucus layer and too many sodium ions moving into the cell. When too many sodium ions move into the cell it drys out the mucus layer by causing the water to move back into the cell. The mucus layer becomes thick and sticky, preventing the cilia from clearing the debris. This leads to infection in many CF patients. The two types of CFTR protein defects are a G551D-CFTR protein defect and a F508del mutation. The G551D-CFTR protein devect affects how well the proteins work at the cell surface, while the F508del ''mutation affects the amount of CFTR proteins that are able to reach the cell surface. Is CF a good canidate for Gene Therapy? 1. The condition results from one the mutation in one gene. 2. The gene mutated is known, CFTR. 3. Adding the normal CFTR gene to the infected tissues should fix the problem. Even if the mutated version is still present, it won't prevent the ability of the normal CFTR gene, if present, to work. The only problem with this would be accessing the digestive system. Cystic Fibrosis seem like it would be a very good canidate for gene therapy using an adenovirus. Kalydeco Kalydeco(ivacaftor) is the only FDA-approved medication (Jan 2012) and the first treatment of the G 55 1D protein mutation in CF patients. This is only effective in children over 6 years old and it is not effective for patients with 2 copies of the ''F508del mutation in the CF gene. Kalydeco targets the G551D protein mutation and helps the "gates" of CFTR open more easily. This will help to balance the amount of chloride in and out of the cells, reducing the mucus build up. Kalydeco is not yet a cure, but it can help treat the 4% of CF patients that have this mutation in the US. Kalydeco enhances the sensitization of the channel-opening of epithelial cells that express the G551D-CFTR protein. Side Effects The most common side effects are headache, common cold, stomach pain, diarrhea, rash, nausea, and dizziness. The most serious side effects when using Kalydeco are related to the liver because high liver enzymes are found in the blood when using Kalydeco. Some of the side effects related to the liver are; pain or discomfort in t he upper right stomacharea, yellowing of your skin or the white part of your eyes, loss of appetite, vomiting or nausea, or dark colored urine. Patients that take Kalydeco must have their doctor check their liver before they start taking Kalydeco, every 3 months during the first year of therapy, and then once a year after while continuing to take kalydeco. References Kalydeco Cystic Fibrosis Foundation Blue Cross Blue Shield Kalydeco Utah State: Learn Genetics UK CF gene therapy consortium